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DNA sensor-associat...
DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids
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- Flood, Peter (författare)
- University College Cork, Cork, Ireland
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- Fanning, Aine (författare)
- University College Cork, Cork, Ireland
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- Woznicki, Jerzy A. (författare)
- University College Cork, Cork, Ireland
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- Crowley, Tadhg (författare)
- University College Cork, Cork, Ireland
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- Christopher, Andrea (författare)
- University College Cork, Cork, Ireland
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- Vaccaro, Alessandra (författare)
- University College Cork, Cork, Ireland
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- Houston, Aileen (författare)
- University College Cork, Cork, Ireland; Department of Medicine, University College Cork, Cork, Ireland
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- McSweeney, Sheila (författare)
- University College Cork, Cork, Ireland
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- Ross, Sarah (författare)
- University College Cork, Cork, Ireland
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- Hogan, Aileen (författare)
- University College Cork, Cork, Ireland
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- Brint, Elizabeth (författare)
- University College Cork, Cork, Ireland; Department of Pathology, Cork University Hospital, University College Cork, Clinical Sciences Building, Cork, Ireland
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- Skowyra, Agnieszka (författare)
- University College Cork, Cork, Ireland
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- Bustamante, Milan (författare)
- University College Cork, Cork, Ireland
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- Ambrose, Monica (författare)
- University College Cork, Cork, Ireland
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- Moloney, Gerard (författare)
- University College Cork, Cork, Ireland
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- MacSharry, John (författare)
- University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland; School of Medicine, University College Cork, Cork, Ireland
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- Hammarström, Marie-Louise (författare)
- Umeå universitet,Immunologi/immunkemi
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- Hurley, Margot (författare)
- University College Cork, Cork, Ireland; Department of Medicine, University College Cork, Cork, Ireland
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- Fitzgibbons, Christine (författare)
- University College Cork, Cork, Ireland
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- Quigley, Eamonn M M (författare)
- University College Cork, Cork, Ireland
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- Shanahan, Fergus (författare)
- University College Cork, Cork, Ireland; Department of Medicine, University College Cork, Cork, Ireland
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- Zulquernain, Syed A. (författare)
- University College Cork, Cork, Ireland; Department of Medicine, University College Cork, Cork, Ireland
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- McCarthy, Jane (författare)
- Department of Gastroenterology, Mercy University Hospital, Cork, Ireland
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- Dodson, G Steven (författare)
- Second Genome, CA, Brisbane, United States
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- Dabbagh, Karim (författare)
- Second Genome, CA, Brisbane, United States
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- McRae, Bradford L. (författare)
- Immunology Discovery, Abbvie Bioresearch Center, MA, Worcester, United States
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- Melgar, Silvia (författare)
- University College Cork, Cork, Ireland
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- Nally, Ken (författare)
- University College Cork, Cork, Ireland; School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
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(creator_code:org_t)
- American Physiological Society, 2022
- 2022
- Engelska.
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 323:5, s. G439-G460
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- DNA sensor pathways can initiate inflammasome, cell death, and type I interferon (IFN) signaling in immune-mediated inflammatory diseases (IMIDs), including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC) by analyzing the expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n = 31), inactive UC (n = 31), active UC (n = 33), and a UC single-cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ, and TNF-α on gene expression, cytokine production, and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLR family pyrin domain-containing 3 (NLRP3), caspase, or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes-PYHIN family members [absent in melanoma 2 (AIM2), IFI16, myeloid cell nuclear differentiation antigen (MNDA), and pyrin and HIN domain family member 1 (PYHIN1)- as well as Z-DNA-binding protein 1 (ZBP1), cyclic GMP-AMP synthase (cGAS), and DDX41 was increased in active UC and expressed in a cell type-restricted pattern. Inflammasome genes (CASP1, IL1B, and IL18), type I IFN inducers [stimulator of interferon response cGAMP interactor 1 (STING), TBK1, and IRF3), IFNB1, and type I IFN biomarker genes (OAS2, IFIT2, and MX2) were also increased in active UC. Cotreatment of organoids with IFN-β or IFN-γ in combination with TNFα increased expression of IFI16, ZBP1, CASP1, cGAS, and STING induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.NEW & NOTEWORTHY This study found that patients with active UC have significantly increased colonic gene expression of cytosolic DNA sensor, inflammasome, STING, and type I IFN signaling pathways. The type I IFN, IFN-β, in combination with TNF-α induced JAK-dependent but NLRP3 and inflammasome-independent inflammatory cell death of colonic organoids. This novel inflammatory cell death phenotype is relevant to UC immunopathology and may partially explain the efficacy of the JAKinibs tofacitinib and upadacitinib in patients with UC.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Nyckelord
- colonic organoids
- DNA sensors
- inflammasome
- type I IFN
- ulcerative colitis
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- Av författaren/redakt...
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Flood, Peter
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Fanning, Aine
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Woznicki, Jerzy ...
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Crowley, Tadhg
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Christopher, And ...
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Vaccaro, Alessan ...
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visa fler...
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Houston, Aileen
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McSweeney, Sheil ...
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Ross, Sarah
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Hogan, Aileen
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Brint, Elizabeth
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Skowyra, Agniesz ...
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Bustamante, Mila ...
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Ambrose, Monica
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Moloney, Gerard
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MacSharry, John
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Hammarström, Mar ...
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Hurley, Margot
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Fitzgibbons, Chr ...
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Quigley, Eamonn ...
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Shanahan, Fergus
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Zulquernain, Sye ...
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McCarthy, Jane
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Dodson, G Steven
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Dabbagh, Karim
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McRae, Bradford ...
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Melgar, Silvia
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Nally, Ken
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